Paclitaxel is a cytoskeletal drug commonly used for the treatment of breast, lung, and ovarian cancer. Peripheral neuropathic pain (CIPN) is one of the most common and serious adverse effects experienced by cancer patients treated with paclitaxel. CIPN can be a dose-limiting factor for chemotherapy, leading to premature termination of treatment, thereby influencing survival and quality of life. Currently, no therapies have been identified that address the underlying pathogenic mechanisms such as neurodegeneration; in fact, the current symptomatic therapies are frequently ineffective in mitigating the painful symptoms of CIPN in the majority of patients. Therefore, the identification of alternative forms of therapy is a crucial medical need. The primary objective of this proposal is to identify novel genetic factors that contribute to paclitaxel- induced neuropathy in mice. We observed pronounced paclitaxel-induced CIPN in C57BL/6NJ strain but not in the closely related C57BL/6J substrain. Because the parental substrains are nearly genetically identical, quantitative trait locus (QTL) mapping in an experimental F2 cross (Reduced Complexity Cross; RCC) will greatly facilitate the identification of novel genetic factors that underlie differences in CIPN behaviors. In Aim 1, we will use the RCC to map genomic regions, or QTLs, that are causally associated with susceptibility versus resilience to multiple measures of CIPN. In Aim 2, we will conduct transcriptome analysis via mRNA sequencing (RNA-seq) of spinal and peripheral neuronal regions in control mice and paclitaxel-treated mice from the parental male and female C57BL/6J and C57BL/6NJ substrains. The transcriptome in control mice will aid in identifying differentially expressed, candidate CIPN susceptibility genes underlying the QTLs . Genes that are differentially expressed as a consequence of paclitaxel will reveal changes in the transcriptome relevant to central and peripheral neuronal plasticity and the behaviors/changes that support the long-term establishment of CIPN that may be important for treatment reversal. In Aim 3, we will validate candidate quantitative trait genes and functional variants that influence susceptibility to and establishment of CIPN. These studies will provide rapid genetic and neurobiological insight into CIPN. Future studies will test for translational potential in human genetics, human experimental model systems (e.g., hIPSCs), and new potential therapeutics to combat the debilitating side effects of CIPN in cancer patients.